Multidrug resistance (MDR) is a major problem in the successful treatment of cancers. Over-expression of some members of the ABC (ATP-binding cassette) transporter super family has been suggested as a cause of MDR. One of the members of this family is ABCG2 which is thought to exist in the cell and functions as homo-oligomers of 8-12 subunits(1-3). ABCG2 has also been implicated as playing a role in protecting cancer stem cells from chemotherapy drugs, resulting in drug resistance and the failure of cancer chemotherapy. Anticancer drug substrates of ABCG2 include, but are not limited to, such commonly used anticancer drugs such as: doxorubicin (8S,10S)-10-(4-amino-5-hydroxy-6-methyl-tetrahydro-2H-pyran-2-yloxy)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione) sold under the trade name Adriamycin; mitoxantrone (1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino) ethylamino]-anthracene-9,10-dione); and topotecan ((S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione monohydrochloride) sold under the trade name Hycamtin. Indeed, recent clinical studies have shown that over-expression of ABCG2 in both adult and childhood leukaemia correlates very well with a poor prognosis for the disease.4 Knocking out ABCG2 activity appeared to have no readily apparent adverse effects on the development, biochemistry, and life of mice with this condition. Accordingly, inhibiting or reducing the activity of ABCG2 is unlikely to cause any serious side effects provided that the inhibitor is specific for ABCG2. This makes ABCG2 an ideal target for development of chemo-sensitizing agents for better treatment of drug resistant cancers.
Compared with the well-known drug resistance-causing ABC transporters such as ABCB1 (MDR1/Pgp) and ABCC1 (MRP1), ABCG2 was discovered relatively recently and, thus, few specific inhibitors of ABCG2 have been reported. One of the best known specific ABCG2 inhibitors is the potent mycotoxin Fumitremorgin C (FTC) secreted by Aspergillus fumigatus. However, the neurotoxicity of FTC limits its therapeutic potential. Analogues of FTC that exhibit lower toxicity than FTC have been developed including such compounds as Ko132 and Ko1435; the present inventors are unaware of any clinical trials exhibiting the efficacy of these molecules. Other inhibitors of ABCG2 have also been reported.6,7 However, some of these reagents, such as GF120918, appear to lack specificity due to their effect on ABCB1 and/or ABCC1.8,9 Clearly then, there is a need for more specific ABCG2 inhibitors to better treat drug resistant cancers. Aspects of the current invention seek to address the need discussed above.